Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis.
Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis.
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DOI：
10.1186/1476-4598-11-84
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发表时间：
2012-11-17
期刊：
影响因子：
37.3
通讯作者：
Piché A
中科院分区：
文献类型：
--
作者：
Goncharenko-Khaider N;Matte I;Lane D;Rancourt C;Piché A
腹水可能影响卵巢癌（OC）的进展。特别是，OC腹水中存在的可溶性因子可以为肿瘤细胞创造一个保护环境，促进对药物和死亡受体诱导的细胞凋亡的从头抵抗。然而，腹水诱导耐药性的潜在分子机制尚未得到很好的表征。使用人类 OC 细胞系和人类 OC 活检组织微阵列，我们使用蛋白质印迹、ERK 化学抑制剂和小抑制性 RNA 治疗评估了 OC 腹水增加 Mcl-1 表达的机制。在本研究中，我们发现用晚期 OC 女性腹水处理 OC 细胞后，Mcl-1 mRNA 和蛋白质水平在 2 小时内上调。相比之下，其他Bcl-2家族抗凋亡成员如Bcl-2和Bcl-XL的表达不受腹水的影响。在晚期浆液性 OC 女性的不同腹水中一致观察到 Mcl-1 表达增加。 Mcl-1 的敲低显着阻断了腹水诱导的 Mcl-1 上调以及腹水介导的 TRAIL 诱导的细胞凋亡的抑制。腹水诱导 ERK1/2 和 Elk-1 转录因子快速磷酸化。此外，我们发现 ERK1/2 抑制或 Elk-1 敲低足以阻断腹水诱导的 Mcl-1 表达。在高级别浆液性 OC 中，我们发现磷酸化 ERK1/2 和 Mcl-1 表达之间呈正相关。这些结果表明，腹水诱导的 ERK1/2/Elk-1 信号传导对于 Mcl-1 表达和腹水介导的 TRAIL 诱导细胞凋亡的减弱至关重要。 ERK1/2/Elk-1/Mcl-1 通路代表了腹水在 OC 细胞中诱导 TRAIL 耐药性的一种新机制。
Ascites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promote de novo resistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized. Using human OC cell lines and tissues microarrays of human OC biopsies, we assessed the mechanism by which OC ascites increase Mcl-1 expression using Western blots, chemical inhibitors of ERK and small-inhibitory RNA treatments. In the present study, we found that both Mcl-1 mRNA and protein levels were upregulated within 2 h upon treatment of OC cells with ascites obtained from women with advanced OC. In contrast, the expression of other Bcl-2 family antiapoptotic members such as Bcl-2 and Bcl-XL was not affected by ascites. An increase of Mcl-1 expression was consistently observed across different ascites from women with advanced serous OC. The knockdown of Mcl-1 significantly blocked ascites-induced Mcl-1 upregulation and ascites-mediated inhibition of TRAIL-induced apoptosis. Ascites induced a rapid phosphorylation of ERK1/2 and Elk-1 transcription factor. Furthermore, we found that ERK1/2 inhibition or Elk-1 knockdown was sufficient to block ascites-induced Mcl-1 expression. In high grade serous OC, we found a positive correlation between phosphorylated ERK1/2 and Mcl-1 expression. These results indicate that ascites-induced ERK1/2/Elk-1 signaling is critical for Mcl-1 expression and for the ascites-mediated attenuation of TRAIL-induced apoptosis. The ERK1/2/Elk-1/Mcl-1 pathway represents a novel mechanism by which ascites induce de novo TRAIL resistance in OC cells.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
8
作者：
Dong, L.;Jiang, C. C.;Thorne, R. F.;Croft, A.;Yang, F.;Liu, H.;de Bock, C. E.;Hersey, P.;Zhang, X. D.
通讯作者：
Zhang, X. D.
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
4.7
作者：
Dodier, P;Piché, A
通讯作者：
Piché, A
影响因子：
4.8
作者：
Clohessy, JG;Zhuang, JG;Brady, HJM
通讯作者：
Brady, HJM